Urinary urgency with intolerable uresiesthesia significantly limits the quality of life (QOL). It is known that patients with pollakiuria (i.e. urinary frequency) accompanied by urinary urgency are very frequent among patients complaining dysuria. Although pathological causes thereof have not been fully elucidated, it is considered that neurogenic or non-neurogenic detrusor (bladder smooth muscle) overactivity constitutes common background. Recently, overactive bladder (OAB) is defined as “urgency, with or without urge incontinence, usually with frequency and nocturia.” by the International Continence Society (Neurourol. Urodyn., 2002). Recently, According to the definition, OAB represents those symptoms expressed by overactivity of detrusor, which does not necessarily need diagnosis based on a uroflometry test, and is understood as a syndrome accompanied by one or more of the symptoms mentioned above in addition to urinary urgency.
As therapeutic agents for OAB, muscarinic acetylcholine receptor antagonists (anticholinergic drugs) have so far been mainly developed and clinically applied. However, it is considered that they do not fully satisfy medical needs, because their effects per se are not sufficient, and moreover, adverse reactions deriving from the anticholinergic action such as mouth dryness and constipation are not satisfactorily eliminated.
Therapeutic agents for OAB, having a completely different mode of action from that of the anticholinergic drugs, have also been researched. It is suggested that prostaglandin E2 (PGE2) constricts the bladder smooth muscle itself through the EP1 receptor, and also acts on the sensory nerve as an afferent nerve system in the bladder to accelerate urination reflex, and thereby induce pollakiuria. A so-called hyperesthetic state is involved in the expression of urinary urgency, and one of examples of the causes of hyperesthesia in OAB or interstitial cystitis is involvement of urinary tract epithelium in excitatory regulation of sensory nerve terminals. Various substances such as adenosine triphosphate (ATP), PG, acetylcholine, tachykinin, vasoactive intestinal peptide (VIP), and nitric oxide (NO) are released form the urinary tract epithelium, and it is believed that PG especially has effects on the excitability of sensory nerve terminals to cause hyperesthesia. Therefore, a curative effect for OAB is expected for PGE2 production suppressors.
It is already known that, for example, cyclooxygenase (COX) inhibitors having a PG production suppressing action such as acetylsalicylic acid (aspirin, salicylic acid type antiinflammatory agent), indomethacin (indoleacetic acid type antiinflammatory agent), flurbiprofen (propionic acid type antiinflammatory agent), ibuprofen (propionic acid type antiinflammatory agent), mefenamic acid (fenum type antiinflammatory agent), and diclofenac (phenylacetic acid type antiinflammatory agent), i.e., nonsteroidal antiinflammatory drugs (NSAIDs), have a pollakiuria improving effect (British Medical Journal, 2, pp. 281-282, 1980; Journal of International Medical Research, 11, pp. 11-17, 1983; Clinical and Experimental Pharmacology & Physiology, 13, pp. 139-142, 1986; Journal of Urology, 142, pp. 1290-1292, 1989; Presse Medicale, 24, pp. 31-34, 1995; BJU International, 88, pp. 126-127, 2000). The article in British Medical Journal (1980) mentioned above describes that “oncoming prostaglandin synthesis inhibitors will be more potent, and accordingly, they will be more effective also for unstable bladder.”
It was also reported that loxoprofen (propionic acid type antiinflammatory agent), which is one of the antipyretic analgesics currently most widely used in Japan, was also effective for nocturia patients (Abstracts of the general meeting in the 90th convention of the Japanese Urological Association (2002) PP-585, Journal of Japanese Urological Association, 93, p. 394, 2002; Abstracts of the 24th annual meeting of the Japanese Society of Clinical Pharmacology and Therapeutics (2003), Japanese Journal of Clinical Pharmacology and Therapeutics, 35, 175S, 2004; Acta Medica Okayama, 58, pp. 45-49, 2004; U.S. Patent Published Application US2004/0054008).
Since NSAIDs including the medicaments mentioned above have modes of action different from that of the anticholinergic drugs, the adverse reactions caused by the anticholinergic action, such as mouth dryness and constipation observed for the anticholinergic drugs, can be avoided. However, available NSAIDs have damaging action on gastrointestinal tract (haemorrhage of digestive tract, ulcer, epigastric distress, abdominal pain, nausea and emesis, anorexia, stomatitis and the like), and the medicaments, including loxoprofen considered to have relatively weak damaging action (Oyo Yakuri (Applied Pharmacology), 21, pp. 753-771, 1981; Yakuri to Chiryo (Japanese Pharmacology & Therapeutics, 14, pp. 5191-5209, 1986), are recommended to be carefully used. Therefore, therapeutic agents for OAB having higher efficacy with superior safety have been desired.
[Non-patent document 1] Neurourol. Urodyn., 21, pp. 167-178, 2002
[Non-patent document 2] British Medical Journal, 2, pp. 281-282, 1980
[Non-patent document 3] Journal of International Medical Research, 11, pp. 11-17, 1983
[Non-patent document 4] Clinical and Experimental Pharmacology & Physiology, 13, pp. 139-142, 1986
[Non-patent document 5] Journal of Urology, 142, pp. 1290-1292, 1989
[Non-patent document 6] Presse Medicale, 24, pp. 31-34, 1995
[Non-patent document 7] BJU International, 88, pp. 126-127, 2000
[Non-patent document 8] Abstracts of the general meeting in the 90th convention of the Japanese Urological Association (2002) PP-585, Journal of Japanese Urological Association, 93, p. 394, 2002
[Non-patent document 9] Abstracts of the 24th annual meeting of the Japanese Society of Clinical Pharmacology and Therapeutics (2003), Japanese Journal of Clinical Pharmacology and Therapeutics, 35, 175S, 2004
[Non-patent document 10] Acta Medica Okayama, 58, pp. 45-49, 2004
[Patent document 1] U.S. Patent Published Application US2004/0054008